Epithelial cancers are the most common ones. They all stem from a hypertrophic growth of cells making up the epithelia, or linings, of internal organs, and the skin. These include skin, lung, stomach, colon and bladder cancer.
Skin cancers in their various forms account for the most frequent cancers. Only one of them, melanoma, is seriously life threatening. Non-melanoma cancers such as basal cell carcinomas (BCC) although very common are relatively benign; squamous cell carcinomas (SCC) are intermediate in danger because they can occasionally metastasise. Hyperplasias such as actinic keratosis (AK) are so called precancerous lesions because they can lead to SCC if left untreated.
Apart from these, there are other conditions that are not life threatening but are the cause of much distress for the patient and require treatment. Psoriasis is an autoimmune disease which results in chronic inflammation of patches of skin causing itching and pain. Keloids are instead abnormal scars which grow to many times the size of the original wound on susceptible individuals. The main treatment is surgical removal but this unavoidably results in another wound with a 50% chance of the keloid returning. A non invasive treatment would be most needed.
With the exception of melanoma, all these conditions affect the outer layers of the skin (epidermis) and are therefore amenable to topical cures as their modest thickness allows access to skin penetrating formulations.
Internal cancers such as lung and the digestive tract (stomach/colon) both represent major causes of mortality and a significant percentage of all cancer deaths. Even though modern preventive approaches have succeeded in reducing incidence, on the therapy side little has been done in terms of specificity of treatment, i.e. non-chemotherapeutic approaches. These cancers all present an interface to air, which makes them potentially accessible to a light emitting probe and therefore to photodynamic therapy.
Photodynamic therapy (PDT) is a novel treatment for hyperproliferative diseases of the skin and internal epithelia. It involves the administration, topical or systemic, of a photosensitive agent which will ideally concentrate in the proliferating tissues of the body. The compound itself is inactive but upon irradiation with a light of a specific wavelength the molecule is chemically activated and stimulated to undergo chemical reactions which either damage the cell directly or result in the production of species that in turn destroy the cells. This way the chemotherapeutic action is physically confined to an area of interest instead of extending to the whole body of the patient with unpleasant and harmful side effects. The field of applicability of photodynamic therapy is naturally limited by the accessibility of tissue to the light source.
Current agents for photodynamic therapy are mainly based on the porphyrin molecule, a derivative of haemoglobin. This molecule absorbs light in the red region of the spectrum and, as a result, is excited into a chemically reactive singlet state. It subsequently releases this energy to molecular oxygen, abundant in cells, turning it into the reactive singlet oxygen molecule. Singlet oxygen in turn causes widespread damage to cellular biomolecules, resulting in cell death.
The compounds in the PDT field today are porphymer sodium (PHOTOPRIN™) and 5-aminolevulinic acid (ALA). PHOTOPRIN™ is a porphyrin derivative which has been licensed for systemic use in the United States and Europe for the treatment of bronchial, lung, bladder and oesophageal cancer. ALA instead is a porphyrin precursor which is converted into protoporphyrin IX directly in cells; it is administered topically and it is licensed for the treatment of actinic keratosis. Its mode of administration involves applying the emulsion on the affected area, then following 14 hours irradiate with red light. An ALA derivative, methyl aminolevulinate (MAL) has been developed and, under the trade name METVIX™, is in use for pre-malignant conditions of the skin (such as basal cell carcinomas and actinic keratosis).
A major disadvantage of the systemic approach (such as PHOTOPRIN™) is the slow clearance of the drug which means that patients cannot be exposed to sunlight or strong lights for many days after treatment. Due to the nature of the molecules themselves, they do not play a biological role in cells. Thus, the molecules do not have the ability to target the proliferating cells as desired.
Recently, a new approach to photodynamic therapy has been introduced. In a recent literature reference, the molecule 4-thiothymidine (4-TT) was described (see Karran P. et al., “Photoactivation of DNA thiobases as a potential novel therapeutic option”, Current Biology, 11(14), 1142-6 (2001)). This molecule is a derivative of thymidine. Thymidine is a pyrimidine nucleotide, one of the four building monomers of DNA. As such, it is needed by all cells in a state of proliferation in order to replicate their DNA. Upon exposure to UV-B, the harmful form of ultraviolet radiation, thymidine undergoes a photochemical reaction which leads to its dimerization to form thymidine dimers, a potentially DNA damaging species. This is why the skin needs protection from UV-B, which is present in small amounts in sunlight. On the contrary, the UV-A fraction of sunlight is harmless to thymidine and DNA. 4-thiothymidine (4-TT) shares with its parent nucleotide the ability to concentrate in proliferating cells but not in normal tissue. Besides, it has the remarkable distinction to be able to absorb in the near UV (UV-A), a region of the spectrum which is quite harmless to normal DNA and cells, and to chemically react with and damage the surrounding DNA once exposed to said radiation. It is foreseen therefore that the species would concentrate in the cells making up the hyperproliferative lesion but not in the surrounding normal tissue. The subsequent irradiation of said tissue with UV-A light ensures that only those cells responsible for the hyperplasia would be targeted and killed.
Research by Karran P. et al. has illustrated the potential for the use of a novel thymidine derivative, 4-thiothymidine (4-TT), in the fight against cancer. This modified thymidine molecule displays a shift in its absorbance peak from 260 nm (UV-B) to 335 nm (UV-A). Excitation of the cells containing 4-thiothymidine (4-TT) at this wavelength will cause the cells to undergo a photochemical reaction producing toxicity in the cells. This modified molecule is an excellent candidate for photodynamic therapy, particularly with its ability as a nucleotide to concentrate in proliferating cells' DNA which provides it with an advantage over other PDT drugs. In fact, since the skin is the only area where the patients will be exposed to ambient light, no significant amount of 4-thiothymidine (4-TT) will be accumulated after treatment because the skin is not hyperproliferative. Moreover, the fact that UV-A radiation is less common than red light and requires direct exposure to sunlight, makes the issue of side effects and patient protection even less relevant. The precautions associated with the use of PHOTOPRIN™ would therefore ideally not be applicable to this new drug.
The employment of nucleotide analogs for the treatment of disease is established in medical practice and particularly in cancer research. Drugs such as fluorouracil and cytarabine are already in use in chemotherapy. Sulfo derivatives of nucleotides are also already known in the art, for example, Azathioprim (IMURAN™) is in use as an antimetabolite for immunosuppression. This molecule is however a nucleotide analog toxic on its own account and does not require photoactivation. The novelty brought about by the 4-TT molecule is in that it is technically a prodrug. Its metabolism, DNA incorporation and base pairing are compatible with its natural analog thymidine and so it is not initially toxic like the other molecules mentioned above. Its toxicity is only revealed following UV irradiation and only where this irradiation occurs.
It is therefore an object of the present invention to provide compositions comprising certain compounds which are biological precursors of thymidine, especially precursors of 4-TT, and which can be used in the photodynamic treatment of skin and internal epithelia hyperplasias. Such compounds are termed “biological precursors” since, once delivered, they are metabolised by normal physiological pathways to form the active molecule.